1H-nuclear magnetic resonance analysis reveals dynamic changes in the metabolic profile of patients with severe burns

Abstract

Background: Severe burn injury causes a hypermetabolic response, resulting in muscle protein catabolism and multiple organ damage syndrome. However, this response has not yet been continuously characterized by metabolomics in patients. This study aims to quantify temporal changes in the metabolic processes of patients with severe burns. Methods: We employed¹H-nuclear magnetic resonance (NMR) spectroscopy to scrutinize metabolic alterations during the initial 35 days following burn injury in a cohort of 17 adult patients with severe burns, with 10 healthy individuals included as controls. Plasma specimens were collected from patients on postburn days 1, 3, 7, 14, 21, 28 and 35. After performing multivariate statistical analysis, repeated-measures analysis of variance and time-series analysis, we quantified changes in metabolite concentrations. Results: Among the 36 metabolites quantified across 119 samples from burn patients, branched-chain amino acids, glutamate, glycine, glucose, pyruvate, lactate, trimethylamine N-oxide and others exhibited obvious temporal variations in concentration. Notably, these metabolites could be categorized into three clusters based on their temporal characteristics. The initial response to injury was characterized by changes in lactate and amino acids, while later changes were driven by an increase in fatty acid catabolism and microbial metabolism, leading to the accumulation of ketone bodies and microbial metabolites. Conclusions: Metabolomics techniques utilizing NMR have the potential to monitor the intricate processes of metabolism in patients with severe burns. This study confirmed that the third day after burn injury serves as the boundary between the ebb phase and the flow phase. Furthermore, identification of three distinct temporal patterns of metabolites revealed the intrinsic temporal relationships between these metabolites, providing clinical data for optimizing therapeutic strategies.

Keywords

Metabolomics / Burn / NMR / Longitudinal data

References

[1] Williams FN, Herndon DN, Jeschke MG. The hypermetabolic response to burn injury and interventions to modify this response. Clin Plast Surg. 2009; 36: 583-96.

[2] Forjuoh SN. Burns in low-and middle-income countries: a review of available literature on descriptive epidemiology, risk factors, treatment, and prevention. Burns. 2006; 32: 529-37.

[3] Peck MD, Kruger GE, van der Merwe AE, Godakumbura W, Ahuja RB. Burns and fires from non-electric domestic appliances in low and middle income countries Part I. The scope of the problem. Burns. 2008; 34: 303-11.

[4] Khan N, Kaur S, Knuth CM, Jeschke MG. CNS-spleen axis-a close interplay in mediating inflammatory responses in burn patients and a key to novel burn therapeutics. Front Immunol. 2021; 12: 720221.

[5] Jeschke MG, van Baar ME, Choudhry MA, Chung KK, Gibran NS, Logsetty S. Burn injury. Nat Rev Dis Primers. 2020; 6: 11.

[6] Jeschke MG, Gauglitz GG, Kulp GA, Finnerty CC, Williams FN, Kraft R, et al. Long-term persistance of the pathophysiologic response to severe burn injury. PLoS One. 2011; 6: e21245.

[7] Minei JP, Nathens AB, West M, Harbrecht BG, Moore EE, Shapiro MB, et al. Inflammation and the host response to injury, a large-scale collaborative project: patient-oriented research core-standard operating procedures for clinical care. II. guidelines for prevention, diagnosis and treatment of ventilator-associated pneumonia (VAP) in the trauma patient. J Trauma. 2006; 60: 1106-13.

[8] Peltz ED, Moore EE, Zurawel AA, Jordan JR, Damle SS, Redzic JS, et al. Proteome and system ontology of hemorrhagic shock: exploring early constitutive changes in postshock mesenteric lymph. Surgery. 2009; 146: 347-57.

[9] Peltz ED, D’Alessandro A, Moore EE, Chin T, Silliman CC, Sauaia A, et al. Pathologic metabolism: an exploratory study of the plasma metabolome of critical injury. J Trauma Acute Care Surg. 2015; 78: 742-51.

[10] Parent BA, Seaton M, Sood RF, Gu H, Djukovic D, Raftery D, et al. Use of metabolomics to trend recovery and therapy after injury in critically ill trauma patients. JAMA Surg. 2016; 151: e160853.

[11] Yang Y, Su S, Zhang Y, Wu D, Wang C, Wei Y, et al. Effects of enteral nutrition with different energy supplies on metabolic changes and organ damage in burned rats. Burns Trauma. 2022; 10: 42.

[12] Hendrickson C, Linden K, Kreyer S, Beilman G, Scaravilli V, Wendorff D, et al. ¹H-NMR Metabolomics identifies significant changes in metabolism over time in a porcine model of severe burn and smoke inhalation. Meta. 2019; 9: 142.

[13] Blaise BJ, Gouel-Chéron A, Floccard B, Monneret G, Allaouchiche B. Metabolic phenotyping of traumatized patients reveals a susceptibility to sepsis. Anal Chem. 2013; 85: 10850-5.

[14] Zhang Y, Cai B, Jiang H, Yan H, Yang H, Peng J, et al. Use of¹H-nuclear magnetic resonance to screen a set of biomarkers for monitoring metabolic disturbances in severe burn patients. Crit Care. 2014; 18: R159.

[15] Serkova N, Klawitter J, Niemann CU. Organ-specific response to inhibition of mitochondrial metabolism by cyclosporine in the rat. Transpl Int. 2003; 16: 748-55.

[16] Brindle JT, Antti H, Holmes E, Tranter G, Nicholson JK, Bethell HW, et al. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using¹H-NMR-based metabonomics. Nat Med. 2002; 8: 1439-45.

[17] Luo G, Peng Y, Yuan Z, Cheng W, Wu J, Tang J, et al. Fluid resuscitation for major burn patients with the TMMU protocol. Burns. 2009; 35: 1118-23.

[18] Xie WG, Li A, Wang SL. Estimation of the calorie requirements of burned Chinese adults. Burns. 1993; 19: 146-9.

[19] Yizhi P, Jing C, Zhiqiang Y, Xiaolu L, Gaoxing L, Jun W, et al. Editorial Board of Guidelines for the Treatment of Burn Infection, Chinese Medical Association. Diagnostic criteria and treatment protocol for post-burn sepsis. Crit Care. 2013; 17: 406.

[20] Ernst J, Bar-Joseph Z. STEM: a tool for the analysis of short time series gene expression data. BMC Bioinformatics. 2006; 7: 191.

[21] Shirani KZ, Vaughan GM, Mason AD, jr, Pruitt BA, jr. Update on current therapeutic approaches in burns. Shock. 1996; 5: 4-16.

[22] Nunez JH, Clark AT. Burn Patient Metabolism and Nutrition. Phys Med Rehabil Clin N Am. 2023; 34: 717-31.

[23] Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular Biology of the Cell. 4th edition. Analyzing Protein Structure and Function New York: Garland Science; 2002. https://www.ncbi.nlm.nih.gov/books/NBK26820/.

[24] Liu Z, Barrett EJ. Human protein metabolism: its measurement and regulation. Am J Physiol Endocrinol Metab. 2002; 283: E1105-12.

[25] Lee-McMullen B, Chrzanowski SM, Vohra R, Forbes SC, Vandenborne K, Edison AS, et al. Age-dependent changes in metabolite profile and lipid saturation in dystrophic mice. NMR Biomed. 2019; 32: e4075.

[26] Porter C, Tompkins RG, Finnerty CC, Sidossis LS, Suman OE, Herndon DN. The metabolic stress response to burn trauma: current understanding and therapies. Lancet. 2016; 388: 1417-26.

[27] Knuth CM, Auger C, Jeschke MG. Burn-induced hypermetabolism and skeletal muscle dysfunction. Am J Physiol Cell Physiol. 2021; 321: C58-71.

[28] Ogunbileje JO, Porter C, Herndon DN, Chao T, Abdelrahman DR, Papadimitriou A, et al. Hypermetabolism and hypercatabolism of skeletal muscle accompany mitochondrial stress following severe burn trauma. Am J Physiol Endocrinol Metab. 2016; 311: E436-48.

[29] Xue CY, Jiang H, Chen W, Dai XS, Jia ZY, Peng X, et al. Expert recommendations on the clinical application of glutamine in critically ill patients (excerpt). J Nutr. 2016; 5: 421-6.

[30] Peng X. Emphasizing the standardized application of glutamine in clinical management of burn injuries. Parenteral and Enteral Nutrition. 2021; 1: 1-4.

[31] Cynober L, Dinh FN, Blonde F, Saizy R, Giboudeau J. Plasma and urinary amino acid pattern in severe burn patients-evolution throughout the healing period. Am J Clin Nutr. 1982; 36: 416-25.

[32] Cynober L, Nguyen Dinh F, Saizy R, Blonde F, Giboudeau J. Plasma amino acid levels in the first few days after burn injury and their predictive value. Intensive Care Med. 1983; 9: 325-31.

[33] Zhang Y, Lv SJ, Yan H, Wang L, Liang GP, Wan QX, et al. Effects of glycine supplementation on myocardial damage and cardiac function after severe burn. Burns. 2013; 39: 729-35.

[34] Aguayo-Cerón KA, Sánchez-Muñoz F, Gutierrez-Rojas RA, Acevedo-Villavicencio LN, Flores-Zarate AV, Huang F, et al. Glycine: the smallest anti-inflammatory micronutrient. Int J Mol Sci. 2023; 24: 11236.

[35] Nakazawa H, Wong LP, Shelton L, Sadreyev R, Kaneki M. Farnesysltransferase inhibitor prevents burn injury-induced metabolome changes in muscle. Meta. 2022; 12: 800.

[36] Osborne T, Wall B, Edgar DW, Fairchild T, Wood F. Current understanding of the chronic stress response to burn injury from human studies. Burns Trauma. 2023; 11: tkad007.

[37] Soto-Heredero G, de Las Heras MM, Gabandé-Rodríguez E, Oller J, Mittelbrunn M. Glycolysis-a key player in the inflammatory response. FEBS J. 2020; 287: 3350-69.

[38] Badoiu SC, Miricescu D, Stanescu-Spinu II, Ripszky Totan A, Badoiu SE, Costagliola M, et al. Glucose metabolism in burns-what Happens? Int J Mol Sci. 2021; 22: 5159.

[39] Gauglitz GG, Herndon DN, Jeschke MG. Insulin resistance postburn: underlying mechanisms and current therapeutic strategies. J Burn Care Res. 2008; 29: 683-94.

[40] Cree MG, Fram RY, Barr D, Chinkes D, Wolfe RR, Herndon DN. Insulin resistance, secretion and breakdown are increased 9 months following severe burn injury. Burns. 2009; 35: 63-9.

[41] Puchalska P, Crawford PA. Metabolic and signaling roles of ketone bodies in health and disease. Annu Rev Nutr. 2021; 41: 49-77.

[42] Mert S, Bulutoglu B, Chu C, Dylewski M, Lin FM, Yu YM, et al. Multiorgan metabolomics and lipidomics provide new insights into fat infiltration in the liver, muscle wasting, and liver-muscle crosstalk following burn injury. J Burn Care Res. 2021; 42: 269-87.

[43] Ufnal M, Zadlo A, Ostaszewski R. TMAO: A small molecule of great expectations. Nutrition. 2015; 31: 1317-23.

[44] Chen S, Henderson A, Petriello MC, Romano KA, Gearing M, Miao J, et al. Trimethylamine N-oxide binds and activates PERK to promote metabolic dysfunction. Cell Metab. 2019; 30: 1141-1151.e5.

[45] Cai YY, Huang FQ, Lao X, Lu Y, Gao X, Alolga RN, et al. Integrated metagenomics identifies a crucial role for trimethylamine-producing Lachnoclostridium in promoting atherosclerosis. NPJ Biofilms Microbiomes. 2022; 8: 11.

[46] Zhang Y, Wang Y, Ke B, Du J. TMAO: how gut microbiota contributes to heart failure. Transl Res. 2021; 228: 109-25.

[47] Zha X, Su S, Wu D, Zhang P, Wei Y, Fan S, et al. The impact of gut microbiota changes on the intestinal mucus barrier in burned mice: a study using 16S rRNA and metagenomic sequencing. Burns Trauma. 2023; 11: 56.

[48] Chinese Medical Doctor Association Burn Physician Branch, Editorial Board of Burn Infection Diagnosis and Treatment Guidelines.Diagnosis and treatment guidelines for burn infection. Zhonghua Shao Shang Za Zhi. 2012; 28: 3.

[49] Rehou S, de Brito Monteiro L, Auger C, Knuth CM, Abdullahi A, Stanojcic M, et al. Propranolol normalizes metabolomic signatures thereby improving outcomes after burn. Ann Surg. 2023; 278: 519-29.